Using immunological approaches to cancer therapy has been difficult as tumor cells are self-derived and therefore not as immunogenic as exogenous agents such as bacteria and viruses. As a result, the prospects of cancer immunotherapy rely upon the identification of tumor associated antigens (“TAA”) which can be recognized by the immune system. Specifically, target antigens eliciting T cell-mediated responses are of critical interest. This comes from evidence that cytotoxic T lymphocytes (CTLs) can induce tumor regression both in animal models (Kast W. et al (1989) Cell 59:6035; Greendberg. P. (1991) Adv. Immunol. 49:281) and in humans (soon T. et al. (1994) Anna. Rev. Immunol. 12:337). To date, many tumor associated antigens have been identified. These include the antigens MAGE, BAGE, GAGE, RAGE, gp100, MART-1/Melan-A, tyrosinase, carcinoembryonic antigen (CEA) as well as many others (Hong and Kaufman (1999) Clinical Immunology 92:211-223). Some of these tumor associated antigens are discussed below.
The first human tumor associated antigen characterized was identified from a melanoma. This antigen (originally designated MAGE 1) was identified using CTLs isolated from an HLA A1+ melanoma patient to screen HLA A1 target cells transfected with tumor DNA (van der Bruggen P. (1991) Science, 254:1643; these tumor associated antigens are now designated MAGE-A1, MAGE-A2, etc.). Interestingly, MAGE 1 was found to belong to a family of at least 12 closely related genes located on the X chromosome (de Plaen, E. et al. (1994) Immunogenetics 40:360). The nucleic acid sequence of the 11 additional MAGE genes share 65-85% identity with that of MAGE-1 (de Smet, C. at al. (1994) Immunogenetics 39:121). Both MAGE 1 and 3 are present in normal tissues, but expressed only in the testis (de Plaen, E. et al. (1994) Supra; de Smet, C. et al. (1994) Supra; Takahashi, K. et al. (1995) Cancer Res. 55:3478; Chyomey, P. et al. (1995) Immunogenetics 43:97). These initial results have subsequently been extended with the identification of new gene families (i.e. RAGE, BAGE, GAGE), all of which are typically not expressed in normal tissues (except testis) but expressed in a variety of tumor types.
Human carcinoembryonic antigen (CEA) is a 180 kD glycoprotein expressed on the majority of colon, rectal, stomach and pancreatic tumors (Muaro et al. (1985) Cancer Res. 45:5769), some 50% of breast carcinomas (Steward at al. (1974) Cancer 33-1246) and 70% of lung carcinomas (Vincent, R. G. and Chu, T. M. (1978) J. Thor. Cardiovas. Surg. 66:320). CEA was first described as a cancer specific fetal antigen in adenocarcinoma of the human digestive tract in 1965 (Gold, P. and Freeman, S. O. (1965) Exp. Med. 121.439). Since that time, CEA has been characterized as a cell surface antigen produced in excess in nearly all solid tumors of the human gastrointestinal tract. The gene for the human CEA protein has been cloned (Oikawa et at (1987) Biochim. Biophys. Res. 142.511-518; European Application No. EP 0346710). CEA is also expressed in fetal gut tissue and to a lesser extent on normal colon epithelium. The immunogenicity of CEA has been ambiguous, with several studies reporting the presence of anti-CEA antibodies in patients (Gold et al. (1973) Nature New Biology 239:60; Pompecki. R. (1980) Eur. J. Cancer 16:973; Ura et al (1985) Cancer Lett. 25:283; Fuchs et al. (1988) Cancer Immunol. Immunother 26:180) while other studies have not (LoGerfo et al. (1972) Int. J. Cancer 9:344; MacSween, J. M. (1975) Int. J. Cancer 15.246: Chester K. A. and Begent, H. J. (1984) Clin. Exp. Immunol. 58:685).
Gp100 is normally found in melanosomes and expressed in melanocytes, retinal cells, and other neural crest derivatives. The function of gp100 is currently unknown. By mass spectrometry, three immunodominant HLA-A2 binding gp100 epitopes have been identified: g9-154 (amino acids 154-162), g9-209 (amino acids 209-217); and g9-280 (amino acids 280-288). Notably, two of these epitopes (as peptides) have been synthetically altered so as to induce a more vigorous immune response in the original T cell clone: the threonine at position 2 in gp-209 was changed to a methionine, and the alanine residue at position 9 in gp-280 was changed to a valine These changes increase the binding affinity of the epitope-peptides to the HLA-A2 molecule without changing the intrinsic natural epitopes recognized by the T cell receptor (TCR). Rosenberg and colleagues (NIH) have already successfully immunized melanoma patients with one of these modified peptides and have reported achieving objective clinical responses in some patients.
Despite significant advances that have been made with respect to immunological approaches to cancer treatment, there is still a need in the art to improve cancer immunotherapies.